Pyridinium thiomethyl substituted chepholosporin derivatives

ABSTRACT

Novel cephem derivatives represented by the general formula ##STR1## in which the Acyl substituent is a group of the formula ##STR2## wherein Ar is a lipophilic optionally substituted phenyl, naphthyl, pyridyl or benzthiazolyl group; R 1  is selected from certain optionally substituted aliphatic, aromatic, arylaliphatic or sugar moieties and R 2  and R 3  are each independently hydrogen, alkyl or aminoalkylcarbonylamino are gram-positive antibacterial agents, especially useful in the treatment of infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of our U.S. patentapplication Ser. No. 08/388,940, filed Feb. 15, 1995, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to new cephem derivatives representedby the general formula ##STR3## in which the Acyl substituent is a groupof the formula ##STR4## where Ar is an optionally substituted lipophilicphenyl, naphthyl, pyridyl or benzthiazolyl group, R¹ is selected fromcertain optionally substituted aliphatic, aromatic, arylaliphatic orsugar moieties and R² and R³ are each independently hydrogen, alkyl oraminoalkylcarbonylamino. The derivatives are gram-positive antibacterialagents, especially useful in the treatment of diseases caused bymethicillin-resistant Staphylococcus aureus (also referred to below asMRSA or methicillin-resistant S. aureus).

2. Description of the Prior Art

The literature discloses a vast number of cephem derivatives having awide variety of C-3 and C-7 substituents. Applicants are not aware,however, of any literature disclosing compounds with the combination ofC-3 and C-7 substituents found by applicants to give good activityagainst MRSA organisms. There are, however, references which disclosecephalosporins having the type of 7-substituents or the type of3-substituents present in the compounds claimed in the presentapplication.

For example, there are references which disclose applicants' C-7substituents. Among such references disclosing 7-substituents of thetype ##STR5## where Ar is an aromatic group are the following:

U.S. Pat. No. 4,056,676 discloses cephem derivatives of the generalformula ##STR6## where Z is hydrogen or fluorine; and when Z ishydrogen, each of X and Y is hydrogen or chlorine selected so that thephenyl ring is substituted with 1 or 2 chlorine atoms and so that whenone chlorine atom is present said chlorine atom is in the 3-position,and when two chlorine atoms are present said chlorine atoms are in the3,4-, the 3,5- or the 2,5-positions; and when Z is fluorine, saidfluorine is in the 3- or 4-positions of the phenyl ring and each of Xand Y is hydrogen or chlorine selected so that when the phenyl ring issubstituted with 1 or 2 chlorine atoms, one of the chlorine atoms is inthe 3- or 4-position of the phenyl ring; R¹ is hydrogen,dicyclohexylamine, or a pharmaceutically acceptable cation; and R is,inter alia, N-pyridino. Among the compounds specifically disclosed arethose of the formulae: ##STR7## The compounds disclosed are said to beuseful for treating and inhibiting the growth of MRSA organisms.

The cephalosporin derivative of the formula ##STR8## is disclosed inAntimicrobial Agents and Chemotherapy--1966, pg. 573-580 at page 576(Compound No. 48).

J. Antibiotics, 26(12), 737-744, 1973, discloses the compound of theformula ##STR9##

U.K. Patent 998,265 discloses cephem derivatives of the general formula##STR10## in which R¹, taken alone, is --OH, C₁ -C₈ acyloxy, ortertiaryamino, R² is --OH when R¹ is --OH, R² is --OH when R¹ is C₁ -C₈acyloxy, R² is --O-- when R¹ is tertiaryamino, R¹ and R², when takentogether, are --O--, R³ and R⁴ represent hydrogen, alkyl radicals havingfrom 1 to 6 carbon atoms, alkenyl radicals having from 2 to 6 carbonatoms, cycloalkyl radicals having from 5 to 7 carbon atoms, oralkoxyalkyl radicals having from 2 to 6 carbon atoms; n represents 0 to4; and R⁵ represents an alkyl radical having from 1 to 6 carbon atoms,an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, acycloalkyl radical having 5 or 6 carbon atoms, phenyl, β-furyl,β-thienyl, thienyl, or naphthyl, or a fluoro, chloro, bromo, nitro,trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄ alkylmercapto, or C₁ -C₄ alkoxysubstitution product of such radicals.

U.K. Published Application No. 2,007,221 A discloses cephalosporinderivatives of the formula ##STR11## wherein Y is hydrogen, chlorine,bromine, C₁ -C₄ alkyl or C₁ -C₄ alkoxy; Z is a bond, oxygen or sulfur; Wis hydrogen, methyl, amino, hydroxy, SO₃ H or COOR₄ wherein R⁴ ishydrogen or 5-indanyl with the proviso that when Z is oxygen or sulfur,W is other than hydroxy; R₁ is hydrogen or methoxy; R₂ is hydrogen,acetoxy, 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio,tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,3,4-oxadiazol-2-ylthio,5-methyl-1,3,4-oxadiazol-2-ylthio, 1,3,4-triazol-2-ylthio,5-methyl-1,3,4-triazol-2-ylthio, 1,2,3-triazol-5-ylthio, pyridinium or4-aminocarbonylpyridinium; R₃ is hydrogen, a negative charge when R₂ ispyridinium or 4-aminocarbonylpyridinium, a cation of an alkali metal oran alkaline earth metal, ammonium or organic ammonium cations, C₁ -C₄alkyl, (C₂ -C₅ alkanoyloxy)methyl, (C₂ -C₅)alkanoylamino)methyl, [C₂ -C₅alkanoyl(C₁ -C₄ alkoxy)carbonyl(C₁ -C₄ alkyl)-amino-methyl, p-(C₂-alkanoyloxy)benzylamino(C₂ -C₁₅ alkanoyloxy)methyl, (C₁ -C₄alkyl)amino(C₂ -C₁₅ alkanoyloxy)methyl or di(C₁ -C₄ alkyl)amino(C₂ -C₁₅alkanoyloxy)methyl; and pharmaceutically acceptable salts thereof.

U.S. Pat. No. 3,217,000 discloses cephem derivatives of the formula##STR12## wherein Thi is 2-thienyl or 3-thienyl and R is a substituentat the 3 or 4 position of the pyridino ring selected from the groupconsisting of cyano, carboxy, carbamyl, N-methylcarbamyl, carbo(C₁ -C₄alkoxy), hydroxy and (C₁ -C₄)alkanoyl; and the salts thereof withpharmaceutically acceptable acids.

There is also literature disclosing cephalosporins having 3-substituentsof the type ##STR13## where R is an optionally substituted aliphatic oraromatic group. Among such references are those of the following:

U.S. Pat. No. 4,758,557 discloses cephalosporin derivatives of thegeneral formula ##STR14## wherein A represents an alkanoyloxy grouphaving 2-5 carbon atoms; a carbamoyloxy group; an azido group; or anunsubstituted or substituted pyridylthio group of the formula ##STR15##where n is 0 or an integer of 3-5; R¹ and R² may be the same ordifferent and each represents a hydrogen atom, a halogen atom, acarboxyl group or an optionally halogen-substituted lower-alkyl grouphaving 1-5 carbon atoms; or an unsubstituted or substitutedpyridiniumthio group of the formula ##STR16## where n, R¹ and R² havethe same meanings as above; R³ represents a linear or branched-chainalkyl group having 1-5 carbon atoms, a halogen-substituted alkyl group,a cyclopropyl group, a cyclopropylmethyl group, an alkenyl group, anoxygen atom or a group of (--CH₂)_(m) --B where m is an integer of 0-3and B represents a hydroxyl group, an alkoxy group, an amino group, analkyl-substituted amino group, a carboxyl group, a carbamoyl group, asulfonic acid group, a sulfonic acid amide group, a hydroxamic group, acyano group, a thiol group, an alkylthio group, amethanesulfonylaminocarbonyl group or an acetamidosulfonyl group; or anunsubstituted or substituted pyridinium group of the formula ##STR17##where n has the same meaning as above; R⁴ and R⁵ may be the same ordifferent and each represent a hydrogen atom, a linear or branched alkylgroup having 1-5 carbon atoms, a carboxyl group, a carbamoyl group, asulfonic acid group, a sulfonic acid amide group, a linear or branchedalkylthio group having 1-5 carbon atoms, a halogen-substituted alkylthiogroup, a cycloalkanothio group, a carbamoylalkylthio group, analkoxyalkylthio group or an alkyl-substituted aminoalkylthio group; or a5- or 6-membered heterocyclicthio or bicycloheterocyclicthio group ofthe formula

    --S-Het

wherein Het represents an optionally substituted thiazole, isothiazole,1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,3,4-tetrazole,pyrimidine, 1,2,4-triazine, benzothiazole, benzimidazole, benzoxazole,1,3,4-triazaindolidine or 2,3-dihydro-1H-indolidinium group.

Illustrative of the compounds encompassed by U.S. Pat. No. 4,758,557 isMT0703 having the structure ##STR18## which is disclosed in J.Antibiotics 43(2), 189-198, 1990.

U.S. Pat. No. 4,786,633 discloses cephalosporin derivatives of theformula ##STR19## wherein R² is a substituted or unsubstitutedheterocyclic group having 1-3 hetero atoms selected from the groupconsisting of nitrogen and sulfur. The R² group may be, for example, agroup of the formula ##STR20## where R⁴ is lower alkenyl, lower alkyl,or a lower alkyl group substituted with a carbamoyl group and R⁵ and R⁶are the same or different and each represent hydrogen or lower alkyl.

Published European Patent Application 409,164 A2 discloses cephalosporinderivatives of the formula ##STR21## wherein R¹ is an amino group oracylamino; R² is hydrogen or methoxy; R³ is hydrogen or a mono- ordivalent substituent; R⁴ is optionally protected vic-dihydroxyaryl; R⁵is straight or branched lower alkylene; R⁶ is hydrogen, acarboxy-protecting group or a negative charge when combined with Y; X isoxygen, sulfur, or sulfinyl; and Y is an anion or a negative charge whencombined with R⁶ ; and the dotted line shows the presence or absence ofa bond.

SUMMARY OF THE INVENTION

The present invention provides a novel series of cephem derivatives ofthe general formula ##STR22## wherein Ar is an aryl group selected fromthe group consisting of ##STR23## in which R⁴, R⁵, and R⁶ are eachindependently hydrogen, halogen, trihalomethyl, nitro, C₁ -C₆ alkyl,--(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to 6; R⁷is hydrogen or C₁ -C₆ alkyl; R¹ is selected from the group consisting of--CR⁸ R⁹ R¹⁰, --(CH₂)_(n) CONR⁸ R⁹ and --(CH₂)_(n) COR⁸ in which R⁸, R⁹and R¹⁰ are each independently hydrogen, substituted or unsubstituted C₁-C₁₅ alkyl, C₂ -C₁₅ alkenyl or C₂ -C₁₅ alkynyl, substituted orunsubstituted phenyl, phenyl(C₁ -C₆)alkyl, naphthyl or naphthyl(C₁-C₆)alkyl or a sugar moiety of the formula ##STR24## in which saidalkyl, alkenyl or alkynyl group, or the alkyl portion of said phenyl(C₁-C₆)alkyl or naphthyl(C₁ -C₆)alkyl group can be substituted by one ormore hydroxy groups and said phenyl or naphthyl group, or the phenyl ornaphthyl portion of said phenyl(C₁ -C₆)alkyl or naphthyl(C₁ -C₆)alkylgroup can be substituted by one or more hydroxy, C₁ -C₆ alkyl, C₁ -C₆alkoxy, halo or halo(C₁ -C₆)alkyl groups; n is as defined above; R² andR³ are each independently hydrogen, C₁ -C₆ alkyl, or amino(C₁-C₆)alkylcarbonyl-amino; and R¹¹ is hydrogen, an anionic charge or acarboxyl-protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt or prodrug thereof. The compounds offormula I are antibacterial agents useful in the treatment of infectionsin humans and other animals caused by a variety of gram-positivebacteria, particularly methicillin-resistant S. aureus.

Also included in the invention are processes for preparing the compoundsof formula I and pharmaceutical compositions containing said compoundsin combination with pharmaceutically acceptable carriers or diluents.

DETAILED DESCRIPTION

The present invention provides novel cephem derivatives of generalformula I above which are antibacterial agents useful in the treatmentof infectious diseases in humans and other animals. The compoundsexhibit good activity against a variety of gram-positive microorganisms,e.g. S. pneumoniae, S. pyrogenes, S. aureus, E. faecalis, E. faecium, S.epidermidis and S. hemolyticus, and are particularly useful againststrains of methicillin-resistant S. aureus.

The compounds of formula I are characterized by a substitutedpyridiniumthiomethyl group of the type ##STR25## at the 3-position ofthe cephem ring and a lipophilic 7-substituent of the type ##STR26##wherein Ar is an aromatic group selected from optionally substitutedphenyl, naphthyl, pyridyl or benzthiazolyl.

To elaborate on the definitions for the substituents of the formula Icompounds:

(a) "Halogen" includes chloro, bromo, fluoro and iodo, and is preferablychloro or bromo;

(b) "Trihalomethyl" includes trichloromethyl, trifluoromethyl,tribromomethyl and triiodomethyl, but is preferably trifluoromethyl;

(c) The aliphatic "alkyl", "alkoxy", "alkenyl" and "alkynyl" groups maybe straight or branched-chains having the specified number of carbonatoms, e.g., in the case of C₁ -C₁₅ alkyl, the alkyl group may have from1 to 15 carbon atoms. It is preferred that the groups have up to 6carbon atoms and most preferably up to 4 carbon atoms.

The term "pharmaceutically acceptable salt" as used herein is intendedto include the nontoxic acid addition salts with inorganic or organicacids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric,maleic, acetic, citric, succinic, benzoic, fumaric, mandelic,p-toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic,trifluoroacetic, hydroiodic, hydrobromic, and the like. Some of thecompounds of the present invention have an acidic hydrogen and can,therefore, be converted with bases in a conventional manner intopharmaceutically acceptable salts. Such salts, e.g. ammonium, alkalimetal salts, particularly sodium or potassium, alkaline earth metalsalts, particularly calcium or magnesium, and salts with suitableorganic bases such as lower alkylamines (methylamine, ethylamine,cyclohexylamine, and the like) or with substituted lower alkylamines(e.g. hydroxyl-substituted alkylamines such as diethanolamine,triethanolamine or tris-(hydroxymethyl)aminomethane), or with bases suchas piperidine or morpholine, are also intended to be encompassed by theterm "pharmaceutically acceptable salt".

Compounds of formula I in the form of acid addition salts may be writtenas ##STR27## where X.sup.⊖ represents the acid anion and R¹¹ is hydrogenor a carboxyl-protecting group. The counter anion X.sup.⊖ may beselected so as to provide pharmaceutically acceptable salts fortherapeutic administration.

The carboxyl-protecting group R¹¹ is intended to include readilyremovable ester groups which have been employed to block a carboxylgroup during the reaction steps used to prepare compounds I and whichcan be removed by methods which do not result in any appreciabledestruction of the remaining portion of the molecule, e.g. by chemicalor enzymatic hydrolysis, treatment with chemical reducing agents undermild conditions, irradiation with ultraviolet light or catalytichydrogenation, etc. Examples of such protecting groups includebenzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl,p-methoxybenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl,acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C₁ -C₆ alkyl such asmethyl, ethyl or t-butyl. Included within such protecting groups arethose which are hydrolyzed under physiological conditions such aspivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, α-acetoxyethyl,α-pivaloyloxyethyl, and methoxymethyl. Compounds of formula I with suchphysiologically hydrolyzable carboxyl protecting groups are alsoreferred to herein and in the claims as "prodrugs". Compounds of formulaI where R¹¹ is a physiologically removable protecting group are usefuldirectly as antibacterial agents. Compounds where an R¹¹ protectinggroup is not physiologically removable are useful intermediates whichcan be easily converted to the active form by conventional deblockingprocedures well-known to those skilled in the art.

Compounds of formula I wherein a hydroxyl group of an R¹ substituent isesterified with a group hydrolyzable under physiological conditions arealso included within the scope of the term "prodrug" as used herein andin the claims. Such hydroxyl protecting groups may be employed, forexample, to increase the solubility of the formula I compound.Illustrative of suitable ester "prodrugs" of this type are compounds offormula I wherein one or more hydroxy groups of the R¹ substituent groupare converted to sulfate (--OSO₃ H) or phosphate (--OPO₃ H₂) groups. Forexample, an R¹ substituent of this type could be --CH₂ CH₂ OSO₃ H or--CH₂ CONHCH₂ CH₂ OPO₃ H₂.

A preferred embodiment of the present invention comprises compounds offormula I wherein Ar is ##STR28## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.

Another preferred embodiment comprises the compounds of formula Iwherein the 3-substituent has the formula ##STR29## wherein R¹ is --CR⁸R⁹ R¹⁰ in which R⁸, R⁹ and R¹⁰ are each independently hydrogen, C₁ -C₆alkyl, hydroxy(C₁ -C₆)alkyl, C₂ -C₆ alkenyl, phenyl(C₁ -C₆)alkyl,hydroxyphenyl(C₁ -C₆)alkyl or dihydroxyphenyl(C₁ -C₆)alkyl; R² and R³are each independently hydrogen, C₁ -C₆ alkyl or amino(C₁-C₆)alkylcarbonylamino; or a pharmaceutically acceptable salt or prodrugthereof. Within this embodiment, the most preferred compounds are thosein which Ar is ##STR30## in which R⁴, R⁵ and R⁶ are each independentlyhydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.

Another preferred embodiment comprises the compounds of formula Iwherein the 3-substituent has the formula ##STR31## wherein R¹ is--(CH₂)_(n) CONR⁸ R⁹ in which R⁸ and R⁹ are each independently hydrogen,hydroxy(C₁ -C₆)alkyl, ##STR32## n is an integer from 1 to 6; and R² andR³ are each independently hydrogen, C₁ -C₆ alkyl or amino(C₁-C₆)alkylcarbonylamino; or a pharmaceutically acceptable salt or prodrugthereof. Within this embodiment, the most preferred compounds are thosein which Ar is ##STR33## in which R⁴, R⁵ and R⁶ are each independentlyhydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.

Another preferred embodiment comprises the compounds of formula Iwherein the 3-substituent has the formula ##STR34## wherein R¹ is--(CH₂)_(n) COR⁸ in which R⁸ is C₁ -C₆ alkyl; n is an integer of from 1to 6; and R² and R³ are each independently hydrogen, C₁ -C₆ alkyl oramino(C₁ -C₆)alkylcarbonylamino; or a pharmaceutically acceptable saltor prodrug thereof. Within this embodiment, the most preferred compoundsare those in which Ar is ##STR35## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.

Another preferred embodiment comprises the compounds of formula Iwherein the 3-substituent has the formula ##STR36## wherein R¹ is##STR37## R² and R³ are each independently hydrogen, C₁ -C₆ alkyl oramino(C₁ -C₆)alkylcarbonylamino; or a pharmaceutically acceptable saltor prodrug thereof. Within this embodiment, the most preferred compoundsare those in which Ar is ##STR38## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.

The preferred individual compounds of the present invention, all ofwhich have an MIC vs a representative MRSA strain of <8 μg/ml, arelisted below:

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)aceta-mido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 1)

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 3)

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 4)

1-(1-Prop-2-enyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 5)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 6)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 7)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 8)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 9)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoro-methylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 10)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(1-naphthylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 11)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-benzthiazolylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 12)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5,6-trichloropyridin-2-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 13)

1-Acetylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 14)

1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 15)

1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 16)

1-(3-Hydroxy-1-propyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 17)

1-(4-Hydroxy-1-butyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 18)

1-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 19)

1-[2-Hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 2)

1-[(N,N-di-2-Hydroxyethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 20)

1-[N-[2-Hydroxy-1-(hydroxymethyl)ethyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 21)

1-[N-2-[2-Deoxy-D-galactopyranosyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 22)

1-[N-3-(3-Deoxy-D-glucopyranosyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 23)

1-[1-(1-Deoxy-D-glucitolyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-phenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 24)

1-[2-(4-Hydroxyphenyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 25)

1-(2-Phosphonoxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 26)

1-(2-Phosphonoxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]-methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 27)

1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-phenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 28)

1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 29)

1-[2-(3,4-Dihydroxyphenyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 30)

1-[2-(Phenylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 31);

1-(2-Hydroxy-1-ethyl)-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 32)

1-[2-(3-Hydroxyphenylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-phenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 33)

1-[2-(3-Methoxy-4-hydroxyphenylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 34)

1-[2-(3,5-Dimethoxy-4-hydroxyphenylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 35); and

1-Methyl-3-aminomethylcarbonylamino-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl)methylthio)]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 36)

The more preferred individual compounds of the present invention, all ofwhich have a MIC≦8 μg/mL and a PD₅₀ ≦5 mg/kg against a representativestrain of MRSA, are listed below:

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 1)

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 3)

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 4)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 7)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 8)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 9)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoro-methylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 10)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(1-naphthylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 11)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-benzthiazolylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 12)

1-Acetylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 14)

1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compoundExample 15)

1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 16)

1-(3-Hydroxy-1-propyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 17)

1-(4-Hydroxy-1-butyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 18)

1-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 19)

1-[2-Hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 2)

1-[(N,N-di-2-Hydroxyethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 20)

1-[N-[2-Hydroxy-1-(hydroxymethyl)ethyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabi-cyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 21)

1-[N-2-[2-Deoxy-D-galactopyranosyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 22)

1-[1-(1-Deoxy-D-glucitolyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 24)

1-[2-(4-Hydroxyphenyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 25)

1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 29); and

1-Methyl-3-aminomethylcarbonylamino-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl)methylthio)]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 36).

The most preferred individual compounds of the present invention arelisted below:

1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 4)

1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 9)

1-[N-[2-Hydroxy-1-(hydroxymethyl)ethyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo-[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 21)

1-[N-2-[2-Deoxy-D-galactopyranosyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 22)

1-[1-(1-Deoxy-D-glucitolyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 24); and

1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 29).

The compounds of the present invention can be made by conventionalmethods. Two suitable procedures are summarized by the followingreaction scheme: ##STR39##

To elaborate on the above processes, thiol VII is converted into thearylthioacetic acid derivative VI, e.g. by treatment with bromoaceticacid under basic conditions (e.g. aqueous sodium or potassiumhydroxide). The reaction temperature for this step is typically between20° and 100° C. Starting thiol VII is commercially available or can beprepared according to known literature procedures. Followingacidification of the reaction mixture, the product VI is typicallyisolated by crystallization or, if necessary, it can be purified bychromatography.

Arylthioacetic acid VI is then coupled with a suitable cephemintermediate having a suitable 3-substituent leaving group. For example,the leaving group may be acetoxy or halo. In the preferred embodimentillustrated by the reaction scheme, the cephem intermediate is the3-chloromethyl cephem V, but other suitable cephem intermediates withequivalent leaving groups at the 3-position could also be employed. Thecephem intermediate V may be acylated with VI or a reactive derivativethereof by conventional acylation procedures well-known in thecephalosporin art to give N-acylated intermediate IV. In addition tousing the free arylthioacetic acid, e.g. with a suitable condensingagent such as dicyclohexylcarbodiimide, acylating agent VI may also beemployed in the form of equivalent acylating derivatives such as an acidanhydride, mixed anhydride, activated ester or acid halide. The cephemintermediate preferably has the carboxyl group protected by aconventional carboxyl-protecting group which can be readily removed.Examples of such protecting groups are discussed above and includebenzyl, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl, allyl, and thelike. Other examples of suitable protecting groups are disclosed inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, 1981), Chapter 5. In one embodiment, intermediate V may beacylated with acid VI in the presence of dicyclohexylcarbodiimide and inan inert solvent such as tetrahydrofuran or dichloromethane. Thereaction temperature is typically between -20° and 50° C. Uponcompletion of the reaction, insoluble material is removed by filtration,the filtrate is concentrated, and the residue is treated with arelatively non-polar solvent such as diethyl ether or ethyl acetateresulting in precipitation of the desired product. Alternatively, acidVI may be converted to the corresponding acid chloride, for example bytreatment with thionyl chloride with or without a solvent such asdichloromethane, followed by coupling with cephem amine V in thepresence of a base such as triethylamine or N-methylmorpholine to giveintermediate IV. Cephem IV is typically isolated by aqueous workupfollowed by trituration of the compound with a relatively non-polarsolvent such as diethyl ether or ethyl acetate. This intermediate may beused in the next reaction step as the X=chloride derivative, or can beconverted to the X=bromide or X=iodide derivative by treatment with theappropriate metal halide in a solvent such as acetone.

Conversion of cephem IV to the target quaternary cephems I may beaccomplished by two different methods. One method entails displacementof an appropriate 3-substituent leaving group with 4-mercaptopyridinefollowed by quaternization of the pyridyl nitrogen, followed bydeprotection of the cephem carboxylate ester. For example, intermediateIV (X=Cl) may be converted to the corresponding iodide by treatment withsodium iodide in a solvent such as acetone at a temperature between -20°and 50° C. The iodide is typically used without purification. Reactionof the iodide with optionally-substituted 4-mercaptopyridine in an inertsolvent such as tetrahydrofuran or dimethylformamide at a temperaturebetween -20° and 50° C. then affords the thiopyridyl derivative II.Alternatively, cephem IV (X=Cl) is treated with optionally substituted4-mercaptopyridine and sodium iodide in a one-pot reaction to giveintermediate II. Reaction of thiopyridyl II with a reactive alkylatingagent provides the quaternary cephem intermediate I'. Examples ofalkylating agents are primary alkyl halides such as methyl iodide,allylic halides such as allyl bromide, halomethyl ethers such aschloromethyl methyl ether and α-halocarbonyl derivatives such asiodoacetamide and 1-bromoacetone. The alkylation reaction is carried outin an inert solvent such as acetone, dimethylformamide ortetrahydrofuran and is run at temperatures between -20° and 100° C.Removal of the cephem carboxylate ester protecting group to give I isthen accomplished under acidic conditions. For example, when R isdiphenylmethyl or 4-methoxybenzyl, I is obtained upon treatment of I'with trifluoroacetic acid neat or in an inert solvent such as methylenechloride. A reagent such as anisole may also be employed to scavenge theliberated ester protecting group. The deprotection may also be carriedout by treatment with other protic acids such as hydrochloric acid in asolvent such as methanol. The final product is typically isolated byprecipitation or crystallization. In some cases, cephem I is purified bycolumn chromatography, for example on reversed-phase adsorbent.

In a second method of preparing quaternary cephems I, intermediate IV isdeprotected under acidic conditions, followed by reaction of theresulting intermediate IV' with a thiopyridone derivative III. Forexample, when R is diphenylmethyl or 4-methoxybenzyl, treatment ofcephem intermediate IV under acidic conditions as described aboveprovides cephem acid IV'. Reaction of IV' with a thiopyridone derivativeIII in a solvent such as dimethylformamide, dimethyl sulfoxide, ethanol,methanol, or other appropriate solvents at a temperature between -20°and 100° C. affords target quaternary cephem I. Thiopyridones III aretypically prepared according to a method analogous to that described inT. Takahashi et al., European Patent Application No. 209751 and I. E.El-Kholy et al., J. Heterocyclic Chem., Vol. 11, p. 487(1974). Thisprocedure entails reaction of 4-thiopyrone (EP 209751) with anappropriate primary amine in a solvent such as aqueous methanol orethanol at a temperature ranging between 0° and 78° C. The primary aminemay be in the form of a zwitterion in cases where there is a free acidgroup present in the molecule. In these cases, a base such as sodiumhydroxide, sodium bicarbonate or pyridine is added to form the freeamine in situ. The product may be isolated as its sodium salt byevaporation of volatile solvents, followed by trituration with a solventsuch as diethyl ether or ethyl acetate. Alternatively, the reactionmixture may be acidified and extracted with an organic solvent to affordthe product as the free carboxylic acid. If the carboxylate group isprotected as an ester, the amine may be free or present as an acid salt.In the latter case, a base such as sodium hydroxide, sodium bicarbonateor pyridine is added to form the free amine in situ. The product istypically isolated by precipitation or by reversed phase columnchromatography following removal of volatile solvents.

Some of the thiopyridone derivatives of formula III are novel compoundsand are intended to be a further aspect of the present invention. Inparticular, the following compounds are encompassed by the presentinvention: ##STR40##

It will be understood that where the substituent groups used in theabove reactions contain certain reaction-sensitive functional groupssuch as amino or hydroxy groups which might result in undesirableside-reactions, such groups may be protected by conventional protectinggroups known to those skilled in the art. Such protecting groups areremoved by conventional procedures known in the art. Suitable protectinggroups and methods for their removal are illustrated, for example, inthe reference work cited above in connection with carboxyl-protectinggroups.

The desired end-product of formula I may be recovered either as thezwitterion or in the form of a pharmaceutically acceptable acid additionsalt, e.g. by addition of the appropriate acid such as HCl, HI ormethanesulfonic acid to the zwitterion. Compounds of formula I where R¹¹is hydrogen or an anionic charge, or a pharmaceutically acceptable saltthereof, may be converted by conventional procedures to a correspondingcompound where R¹¹ is a physiologically hydrolyzable ester group.

The novel cephalosporin derivatives of general formula I wherein R¹¹ ishydrogen, an anionic charge or a physiologically hydrolyzablecarboxyl-protecting group, or the pharmaceutically acceptable salts orprodrugs thereof, are potent antibiotics active against manygram-positive bacteria. While they may be used, for example, as animalfeed additives for promotion of growth, as preservatives for food, asbactericides in industrial applications, for example in waterbased paintand in the white water of paper mills to inhibit the growth of harmfulbacteria, and as disinfectants for destroying or inhibiting the growthof harmful bacteria on medical and dental equipment, they are especiallyuseful in the treatment of infectious disease in humans and otheranimals caused by the gram-positive bacteria sensitive to the newderivatives. Because of their excellent activity against MRSA organisms,they are particularly useful in the treatment of infections resultingfrom such bacteria.

The pharmaceutically active compounds of this invention may be usedalone or formulated as pharmaceutical compositions comprising, inaddition to the active cephem ingredient, a pharmaceutically acceptablecarrier or diluent. The compounds may be administered by a variety ofmeans, for example, orally, topically or parenterally (intravenous orintramuscular injection). The pharmaceutical compositions may be insolid form such as capsules, tablets, powders, etc. or in liquid formsuch as solutions, suspensions or emulsions. Compositions for injection,the preferred route of delivery, may be prepared in unit dose form inampules or in multidose containers and may contain additives such assuspending, stabilizing and dispersing agents. The compositions may bein ready-to-use form or in powder form for reconstitution at the time ofdelivery with a suitable vehicle such as sterile water.

The dosage to be administered depends, to a large extent, on theparticular compound being used, the particular composition formulated,the route of administration, the nature and condition of the host andthe particular situs and organism being treated. Selection of theparticular preferred dosage and route of application, then, is left tothe discretion of the physician or veterinarian. In general, however,the compounds may be administered parenterally or orally to mammalianhosts in an amount of from about 50 mg/day to about 20 g/day.Administration is generally carried out in divided doses, e.g., three tofour times a day, analogous to dosing with a cephalosporin such ascefotaxime.

To illustrate the antibacterial properties of the compounds of thepresent invention, the following biological data is presented below.

IN VITRO ACTIVITY

Samples of the compounds prepared below in Examples 1-36 after solutionin water and dilution with Nutrient Broth were found to exhibit thefollowing ranges of Minimum Inhibitory Concentrations (MIC) versus theindicated microorganisms as determined by tube dilution. The MICs weredetermined using a broth micro dilution assay in accordance with thatrecommended by the National Committee for Clinical Laboratory Standards(NCCLS). Mueller-Hinton medium was used except for Streptococci whichwas tested in Todd Hewitt broth. The final bacterial inoculate containedapproximately 5×10⁵ cfu/ml and the plates were incubated at 35° C. for18 hours in ambient air (Streptococci in 5% CO₂). The MIC was defined asthe lowest drug concentration that prevented visible growth.

    ______________________________________                                                               MIC range in                                           Microorganism          mcg/ml                                                 ______________________________________                                        S. aureus methicillin resistant A27223                                                               0.125-8                                                S. pneumoniae A9585     0.0001-0.06                                           S. pyogenes A9604       0.0001-0.06                                           E. faecalis A20688     0.06-8                                                 E. faecium A24885      0.25-8                                                 S. aureus A9537, penicillinase negative                                                                0.001-0.125                                          S. aureus A15090, penicillinase positive                                                             0.015-1                                                S. epidermidis A24548    0.001-0.125                                          S. epidermidis A25783, methicillin resistant                                                         0.03-1                                                 S. hemolyticus A21638   0.001-0.5                                             S. hemolyticus A27235, methicillin resistant                                                         0.125-8                                                ______________________________________                                    

IN VIVO ACTIVITY

The in vivo therapeutic efficacy of the compounds prepared in Examples1-36 below after intramuscular injection to mice experimentally infectedwith the representative MRSA strain A27223 was also measured.

The determination of the effectiveness of antimicrobial agents inStaphylococcus aureus systemic infection in mice

Organisms:

The test organism, MRSA strain A27223 used to generate systemicinfection in mice, is grown on two large Brain Heart Infusion Agarplates. On each plate, 0.5 ml of frozen stock culture is plated out.Plates are then incubated for 18 hours at 30° C. The next day each plateis washed with 20 ml of Brain Heart Infusion Broth and then pooledtogether. A microscopic direct count of microorganism is done using a1:1000 dilution of plate wash. After a direct count is obtained, thenumber of organisms per milliliter is calculated. The count is adjustedto the desired amount of inoculum by diluting in 4% hog mucin. Thedesired challenge (amount of organisms given to mice) is 2.4×10⁸ cfu/0.5ml/mouse for MRSA strain A27223. The mice are infected intraperitoneallywith 0.5 ml of challenge. Ten non-treated infected mice are used ascontrols.

Mice:

Mice used are male ICR mice. The average weight of the animals is from20 to 26 grams.

Drug preparation and treatment:

Compounds are tested at 4 dose levels, (25, 6.25, 1.56, and 0.39 mg/kg)and prepared in 5% cremophor, unless otherwise specified. Vancomycin isused as the control compound, and is dosed at 6.25, 1.56, 0.39, and0.098 mg/kg. It is prepared in 0.1M phosphate buffer. There are fiveinfected mice per dose level, and they are treated with 0.2 ml of thetest compound, preferably by intramuscular injection. Treatment begins15 minutes and 2 hours post-infection.

Test duration:

A PD₅₀ (the dose of drug given which protects 50% of mice frommortality) runs for 5 days. During this time, mortality of mice arechecked every day and deaths are recorded. The cumulative mortality ateach dose level is used to calculate a PD₅₀ value for each compound.Surviving mice are sacrificed at the end of day 5 by CO₂ inhalation.

Calculation:

Actual calculation of PD₅₀ is performed with a computer program usingthe Spearman-Karber procedure.

Results:

The in vivo efficacy, expressed as the PD₅₀ value, ranged from about 0.6to about 22 mg/kg (for certain compounds, more than one test was carriedout; the indicated range is for at least one test result when multipletests were done).

ILLUSTRATIVE EXAMPLES

The following examples illustrate the invention, but are not intended asa limitation thereof. The abbreviations used in the examples areconventional abbreviations well-known to those skilled in the art. Someof the abbreviations used are as follows:

    ______________________________________                                        h               = hour(s)                                                     mol             = mole(s)                                                     mmol            = mmole(s)                                                    g               = gram(s)                                                     THF             = tetrahydrofuran                                             L               = liter(s)                                                    mL              = milliliter(s)                                               Et.sub.2 O      = diethyl ether                                               EtOAc           = ethyl acetate                                               MeOH            = methanol                                                    DMF             = dimethylformamide                                           ______________________________________                                    

In the following examples, all temperatures are given in degreesCentigrade. Melting points were determined on an electrothermalapparatus and are not corrected. Proton and carbon-13 nuclear magneticresonance (¹ H and ¹³ C NMR) spectra were recorded on a Bruker AM-300 ora Varian Gemini 300 spectrometer. All spectra were determined in CDCl₃,DMSO-d₆, CD₃ OD, or D₂ O unless otherwise indicated. Chemical shifts arereported in δ units relative to tetramethylsilane (TMS) or an internalsolvent peak and interproton coupling constants are reported in Hertz(Hz). Splitting patterns are designated as follows: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd,doublet of doublets and dt, doublet of triplets. Infrared spectra weredetermined on a Perkin-Elmer 1800 FT-IR spectrometer from 4000 cm⁻¹ to400 cm⁻¹, calibrated to 1601 cm⁻¹ absorption of a polystyrene film, andare reported in reciprocal centimeters (cm⁻¹). Mass spectra wererecorded on a Kratos MS-50 or a Finnegan 4500 instrument utilizingdirect chemical ionization (DCI, isobutene) or fast atom bombardment(FAB). Ultraviolet spectra were determined on a Hewlett Packard 8452diode array spectrophotometer in the solvent indicated.

Analytical thin-layer chromatography (TLC) was carried out on precoatedsilica gel plates (60F-254) and visualized using UV light, iodinevapors, and/or staining by heating with methanolic phosphomolybdic acid.Column chromatography, also referred to as flash chromatography, wasperformed in a glass column using finely divided silica gel at pressuressomewhat above atmospheric pressure with the indicated solvents.Reversed-phase analytical thin-layer chromatography was carried out onprecoated reverse phase plates and visualized using UV light or iodinevapors. Reversed-phase column chromatography was performed in a glasscolumn using Baker Octadecyl (C₁₈), 40 μm.

Example 11-Methyl-4-[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)aceta-mido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride ##STR41## A. 2,5-Dichlorophenylthioacetic acid

A mixture of 2,5-dichlorothiophenol (10.3 g, 57.5 mmol) and bromoaceticacid (8.03 g, 57.8 mmol) in water (225 mL) was treated with 10N NaOH (13mL, 130 mmol) and the mixture was heated at 100° C. for 1 h. Thereaction mixture was then cooled to 0° C. and acidified to pH 1 with 6NHCl. The product precipitated and was collected by filtration to give13.0 g (95% yield) of 2,5-dichlorophenylthioacetic acid as whitecrystals, m.p. 118° C. ¹ H NMR (300 MHz, CDCl₃) δ3.74 (s, 2 H), 7.15(dd, J=2, 9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.36 (d, J=2 Hz, 1H). Anal.Calcd. for C₈ H₆ O₂ SCl₂ : C, 40.53; H, 2.55. Found: C, 40.46; H, 2.64.

B.(6R)-trans-3-Chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester

Method a:

A solution of 2,5-dichlorophenylthioacetic acid (13.0 g, 54.9 mmol) inmethylene chloride (55 mL) and thionyl chloride (10 mL, 137 mmol) washeated at reflux for 3 h. The reaction mixture was allowed to cool toroom temperature and was concentrated in vacuo. The residue wasevaporated two times from toluene to give 14 g of2,5-dichlorophenylthioacetyl chloride (100% yield) as a slightly coloredproduct which was used in the next step without purification. ¹ H NMR(300 MHz, CDCl₃) δ4.13 (s, 2H), 7.22 (dd, J=2, 9 Hz, 1H), 7.35 (d, J=9Hz, 1H), 7.39 (d, J=2 Hz, 1H).

(6R)-trans-3-Chloromethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester, HCl salt was stirred in a biphasic mixture ofEtOAc and saturated NaHCO₃ for 0.5 h. The layers were separated, and theorganic solution was dried over anhydrous MgSO₄, filtered, andconcentrated to dryness. The free base (9.15 g, 22.0 mmol) was dissolvedin THF (200 mL), cooled to 0° C., and treated with N-methylmorpholine(3.34 g, 33.0 mmol) and 2,5-dichlorophenylthioacetyl chloride (6.75 g,26.4 mmol). The reaction mixture was stirred for 1 h at 0° C., dilutedwith EtOAc (1000 mL) and washed with water (1000 mL) and brine (100 mL).The organic solution was then dried (MgSO₄) and the solvents wereevaporated in vacuo. The residue was stirred with ether (100 mL). Theproduct solidified and was collected by filtration to give 12.0 g (86%yield) of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester, m.p. 120° C. ¹ H NMR (300 MHz, CDCl₃) δ3.43 (d,J=18 Hz, 1H), 3.59 (d, J=18 Hz, 1H), 3.69 (d, J=17 Hz, 1H), 3.79 (d,J=17 Hz, 1H), 4.36 (d, J=12 Hz, 1H), 4.41 (d, J=12 Hz, 1H), 4.98 (d, J=5Hz, 1H), 5.81 (dd, J=5, 9 Hz, 1H), 6.98 (s, 1H), 7.14-7.44 (m, 14H).Anal. Calcd for C₂₉ H₂₃ N₂ O₄ S₂ Cl₃ : C, 54.94; H, 3.66; N, 4.42.Found: C, 55.18; H, 3.84; N, 4.62.

Method b:

(6R)-trans-3-Chloromethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester, HCl salt (Otsuka, 248 g, 0.55 mol) was treatedwith NaHCO₃ (56 g, 0.66 mol) in water (1.6 L) at 0° C. The mixture wasstirred at 0° C. for 0.5 h and then CH₂ Cl₂ (1.5 L) was added. Thebiphasic mixture was filtered through Celite and the Celite pad waswashed with CH₂ Cl₂ (2 L total). The layers were separated and theorganic solution was dried over anhydrous MgSO₄, filtered, andconcentrated to a volume of ca. 2 L. The free amine solution was thenadded to a mixture of 2,5-dichlorothiophenylacetic acid (130 g, 0.55mol) and dicyclohexylcarbodiimide (144 g, 0.70 mol) in THF (1 L) at roomtemperature. The reaction mixture was stirred for 2.5 h and then wasfiltered through Celite, washing the Celite pad with several portions ofacetone. The filtrate was concentrated in vacuo to give a solid mass.The solid was slurried in Et₂ O and then collected by filtration,washing the solid with several portions of Et₂ O. The solid was driedunder high vacuum over P₂ O₅ to give 268 g (77% yield) of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (see above for analytical data).

C.(6R)-trans-3-(4-Pyridylthiomethyl)-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester

A solution of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (6.00 g, 9.46 mmol) in acetone (100 mL) was treatedwith sodium iodide (4.26 g, 28.4 mmol). The mixture was stirred at 20°C. for 3 h and then condensed under reduced pressure to a volume of 50mL. The concentrated solution was diluted with EtOAc (200 mL) and washedwith ice water (100 mL). The organic solution was washed with saturatedNaHSO₄ (20 mL), dried (MgSO₄), and evaporated under reduced pressure.The residue was stirred with ether (30 mL). The product solidified andwas collected by filtration to give 6.40 g of(6R)-trans-3-iodomethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (93% yield) as a buff solid, m.p. 124° C. ¹ H NMR(300 MHz, CDCl₃) δ3.43 (d, J=18 Hz, 1H), 3.69 (d, J=17 Hz, 1H), 3.70 (d,J=18 Hz, 1H), 3.78 (d, J=17 Hz, 1H), 4.27 (d, J=9 Hz, 1H), 4.33 (d, J=9Hz, 1H), 4.96 (d, J=5 Hz, 1H), 5.75 (dd, J=5, 9 Hz, 1H), 7.00 (s, 1H),7.20-7.46 (m, 14H). Anal. Calcd. for C₂₉ H₂₃ N₂ O₄ S₂ Cl₂ I: C, 8.01; H,3.20; N, 3.86. Found: C, 48.00; H, 3.14; N, 3.76.

(6R)-trans-3-Iodomethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (3.00 g, 4.14 mmol) was dissolved in THF (50 mL) at0° C. and treated with 4-mercaptopyridine (0.504 g, 4.54 mmol). Asolution of 2,6-lutidine (0.576 g, 5.38 mmol) in THF (1 mL) was addednext, and the reaction mixture was stirred at 0° C. for 0.5 h and thenat 20° C. for 1 h. The mixture was diluted with ethyl acetate (500 mL)and the organic solution was washed with water (2×500 mL) and brine (100mL). The solution was then dried (MgSO₄) and evaporated under reducedpressure to give an oil which was treated with Et₂ O (50 mL) to give asolid. The solid was collected by filtration and purified by columnchromatography on silica gel (CH₂ Cl₂ to 30% EtOAc/CH₂ Cl₂) to give 1.50g of(6R)-trans-3-[(4-pyridylthiomethyl]-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester as a tan solid (49% yield), m.p. 122° C. ¹ H NMR(300 MHz, CDCl₃) δ3.37 (d, J=18 Hz, 1H), 3.52 (d, J=18 Hz, 1H), 3.68 (d,J=17 Hz, 1H), 3.76 (d, J=17 Hz, 1H), 3.96 (d, J=13 Hz, 1H), 4.16 (d,J=13 Hz, 1H), 4.93 (d, J=5 Hz, 1H), 5.76 (dd, J=5, 9 Hz, 1H), 6.95-7.42(m, 16H), 7.49 (d, J=9 Hz, 1H), 8.29 (d, J=6 Hz, 2H). Anal. Calcd. forC₃₄ H₂₇ N₃ O₄ S₃ Cl₂ : C, 57.62; H, 3.84; N, 5.93. Found: C, 57.27; H,3.68; N, 5.79.

D.1-Methyl-4-[(6R)-trans-2-(diphenylmethylcarboxy)-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumiodide

A solution of(6R)-trans-3-[(4-pyridylthiomethyl]-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (0.50 g, 0.70 mmol) in dry acetone (50 mL) wastreated with iodomethane (5 mL). The solution was stirred at 20° C. for5 h and the solvents were then evaporated under reduced pressure. Theresidue was treated with ethyl acetate (5 mL), and the resulting solidwas collected by filtration to give 0.48 g of1-methyl-4-[(6R)-trans-2-(diphenylmethylcarboxy)-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumiodide as a tan solid (80% yield), m.p. 110° C. ¹ H NMR (300 MHz, CDCl₃)δ3.55 (d, J=18 Hz, 1H), 3.80 (d, J=18 Hz, 1H), 3.93 (s, 2H), 4.17 (s,3H), 4.22 (d, J=12 Hz, 1H), 4.29 (d, J=12 Hz, 1H), 5.21 (d, J=5 Hz, 1H),5.80 (dd, J=5, 8 Hz, 1H), 6.95 (s, 1H). 7.21-7.48 (m, 13H), 7.84 (d, J=7Hz, 2H), 8.63 (d, J=7 Hz, 2H), 9.32 (d, J=8 Hz, 1H).

E.1-Methyl-4-[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride

A solution of1-methyl-4-[(6R)-trans-2-(diphenylmethylcarboxy)-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumiodide (0.48 g, 0.56 mmol) in methylene chloride (10 mL) was cooled to0° C. and treated with anisole (2 mL) and trifluoroacetic acid (7 mL).The solution was stirred at 0° C. for 1 h and then the solvents wereremoved under reduced pressure. The residue was treated with Et₂ O toafford a tan solid which was purified by treatment with activatedcharcoal and Amberlite IRA-400 (Cl) ion-exchange resin in 1:1methanol-acetone followed by filtration and concentration of thefiltrate to give 0.28 g of1-methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium,HCl salt as a brown solid (85% yield). ¹ H NMR (300 MHz, DMSO-d₆) δ3.49(d, J=18 Hz, 1H), 3.73 (d, J=18 Hz, 1H), 3.91 (s, 2H), 4.17 (s, 3H),4.37 (s, 2H), 5.13 (d, J=5 Hz, 1H), 5.68 (dd, J=5, 8 Hz, 1H), 7.23 (dd,J=2, 8 Hz, 1H), 7.46-7.49 (m, 2H), 7.98 (d, J=7 Hz, 2H), 8.70 (d, J=7Hz, 2H), 9.28 (d, J=8 Hz, 1H). Anal. Calcd. for C₂₂ H₁₉ N₃ O₄ S₃ Cl₂.2.2H₂ O.HCl: C, 41.78; H, 3.89; N, 6.64. Found: C, 41.62; H, 3.62; N, 6.28.

Example 21-[2-Hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride ##STR42## A.(6R)-trans-3-Chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A slurry of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (10.0 g, 15.8 mmol) in CH₂ Cl₂ (200 mL) at 0° C.was treated with anisole (24 mL) and then trifluoroacetic acid (80 mL).The resulting solution was stirred for 1 h at 0° C. and thenconcentrated under reduced pressure. The residue was stirred with Et₂ O,and the resulting solid was collected by filtration to give 5.20 g of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white solid (70% yield), m.p. 125° C. ¹ H NMR (300 MHz,DMSO-d₆) δ3.51 (d, J=18 Hz, 1H), 3.70 (d, J=18 Hz, 1H), 3.91 (s, 2H),4.52 (d, J=11 Hz, 1H), 4.58 (d, J=11 Hz, 1H), 5.13 (d, J=5 Hz, 1H), 5.70(dd, J=5, 8 Hz, 1H), 7.24 (dd, J=2, 8 Hz, 1H), 7.47 (dd, J=2, 8 Hz, 1H),9.28 (d, J=8 Hz, 1H).

B.1-[2-Hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride

A solution of 4-thiopyrone (0.500 g, 4.46 mmol) (ref: European PatentApplication No. 209751) in absolute ethanol (15 mL) was placed under anitrogen atmosphere and treated with tris(hydroxymethyl)aminomethane(0.541 g, 4.46 mmol). The reaction mixture was heated at reflux for 2 h,and then allowed to cool to room temperature. Upon cooling a precipitatewas visible. Acetone (30 mL) was added, and the heterogeneous mixturewas stirred for 1 min. The precipitate was collected by filtration,washed with acetone, and dried in vacuo to give 0.495 g (52% yield) of1-[2-hydroxy-1,1-di(hydroxymethyl)ethyl]-4-thiopyridone as a goldensolid. ¹ H NMR (300 MHz, DMSO-d₆) δ3.78 (d, J=5 Hz, 6H), 5.17 (t, J=5Hz, 3H), 7.13 (d, J=7 Hz, 2H), 7.76 (d, J=7 Hz, 2H); ¹³ C NMR (75 MHz,DMSO-d₆) δ60.91, 71.68, 129.59, 134.69, 188.48; IR (KBr) 3406, 1624,1084 cm⁻¹ ; FAB MS m/z 216 (MH⁺). Anal. Calcd. for C₉ H₁₃ NO₃ S: C,50.22; H, 6.09; N, 6.51. Found: C, 50.13; H, 6.15; N, 6.53.

A solution of 1-[2-hydroxy-1,1-di(hydroxymethyl)ethyl]-4-thiopyridone(0.344 g, 1.60 mmol) in DMF (6 mL) was added to(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (0.702 g, 1.50 mmol). The mixture was stirred for 4 h, and then thesolvent was removed in vacuo, keeping the temperature below 30° C. Thetarry residue was stirred with 40 mL of Et₂ O until a yellow powderresulted. The powder was collected by filtration, and then stirred withacetone for 30 min. The resulting gummy solid was collected byfiltration and washed with Et₂ O. The solid was slurried in acetone for30 min., and then collected by filtration and washed with Et₂ O to give0.700 g of nearly pure product. This material was dissolved in 5-10 mLof methanol, filtered through a plug of cotton, and then diluted withEt₂ O to precipitate a yellow solid. The solid was collected byfiltration, washed with Et₂ O, and dried in vacuo to give 0.499 g (49%yield) of1-[2-hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride as a yellow solid. ¹ H NMR (300 MHz, DMSO-d₆) δ3.53 (d, J=18Hz, 1H), 3.75 (d, J=18 Hz, 1H), 3.92-3.93 (m, 8H), 4.38 (d, J=13 Hz,1H), 4.45 (d, J=13 Hz, 1H), 5.13 (d, J=5 Hz, 1H), 5.50-5.81 (br s, 3H),5.67 (dd, J=5, 8 Hz, 1H), 7.23 (dd, J=2, 8 Hz, 1 H), 7.44-7.48 (m, 2H),7.98 (d, J=7 Hz, 2H), 8.85 (d, J=7 Hz, 2H), 9.30 (d, J=8 Hz, 1H); ¹³ CNMR (75 MHz, DMSO-d₆) δ27.2, 33.5, 34.07, 57.49, 59.31, 60.71, 76.40,122.28, 123.37, 126.15, 126.27, 127.18, 128.81, 130.69, 132.53, 137.88,141.82, 161.56, 162.98, 164.16, 168.22; IR (KBr) 3290, 1776, 1676, 1624,1540, 1094 cm⁻¹ ; FAB MS m/z 646 (MH⁺). Anal. Calcd. For C₂₅ H₂₅ N₃ O₇S₃ Cl₂.HCl.0.75 H₂ O: C, 43.11; H, 3.98; N, 6.03. Found: C, 43.31; H,4.06; N, 5.97.

Following the general procedures shown above, the following thiopyridonederivatives were prepared:

    __________________________________________________________________________    Compound                .sup.1 H NMR DATA               MS                    __________________________________________________________________________                                                            DATA                   ##STR43##              3.35-3.42(m, 1H), 3.44-3.50(m, 2H), 3.52-3.65(m,                              2H), 3.71-3.80(m, 1H), 3.82-3.90(m, 1H), 4.13(dd,                             J=11, 1, 1H), 4.37(t, J=5, 1H), 4.46 (d, J=6,                                 1H), 4.54(d, J=5, 1H), 4.59(d, J=6, 1H), 5.16(d,                              J=5, 1H), 7.13(d, J=7, 2H), 7.51(d, J=7,                                                                      M+ = 275               ##STR44##              4.09-4.15(m, 2H), 4.32-4.36(m, 2H), 7.53(d, J=7,                              2H), 7.82(d, J=7, 2H)           MH = 234               ##STR45##              3.98, (t, J=5, 2H), 4.16(t, J=5, 2H), 7.13(d,                                 J=7, 2H), 7.57(d, J=7, 2H)      MH = 234              __________________________________________________________________________

The following compounds were prepared according to the generalprocedures of Examples 1 and 2 by varying the thiol starting materialand the pyridine or thiopyridone derivative: ##STR46##

    __________________________________________________________________________    Ex. No.                                                                            Ar               R.sup.1            R.sup.2                                                                          R.sup.3   Isolated                __________________________________________________________________________                                                          As                       3   2,4,5-trichlorophenyl                                                                          CH.sub.3           H  H         HCl salt                 4   2,6-dichloropyridin-4-yl                                                                       CH.sub.3           H  H         HI salt                  5   2,4,5-trichlorophenyl                                                                          CH.sub.2 CH═CH.sub.2                                                                         H  H         CF.sub.3 CO.sub.2 H                                                           salt                     6   2,5-dichlorophenyl                                                                             CH.sub.2 CONH.sub.2                                                                              H  H         CF.sub.3 CO.sub.2 H                                                           salt                     7   2,4,5-trichlorophenyl                                                                          CH.sub.2 CONH.sub.2                                                                              H  H         HCl salt                 8   2,6-dichloropyridin-4-yl                                                                       CH.sub.2 CONH.sub.2                                                                              H  H         HI salt                  9   3-bromophenyl    CH.sub.2 CONH.sub.2                                                                              H  H         HCl salt                10   2-chloro-5-trifluoromethylphenyl                                                               CH.sub.2 CONH.sub.2                                                                              H  H         HCl salt                11   1-naphthyl       CH.sub.2 CONH.sub.2                                                                              H  H         HCl salt                12   2-benzthiazolyl  CH.sub.2 CONH.sub.2                                                                              H  H         HCl salt                13   3,5,6-trichloropyridin-2-yl                                                                    CH.sub.2 CONH.sub.2                                                                              H  H         HI salt                 14   2,4,5-trichlorophenyl                                                                          CH.sub.2 C(O)CH.sub.3                                                                            H  H         HI salt                 15   2,5-dichlorophenyl                                                                             CH.sub.2 CH.sub.2 OH                                                                             H  H         HCl salt                16   2,6-dichloropyridin-4-yl                                                                       CH.sub.2 CH.sub.2 OH                                                                             H  H         HCl salt                17   2,5-dichlorophenyl                                                                             CH.sub.2 CH.sub.2 CH.sub.2 OH                                                                    H  H         HCl salt                18   2,5-dichlorophenyl                                                                             CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                                                           H  H         HCl salt                19   2,5-dichlorophenyl                                                                             CH(CH.sub.2 OH).sub.2                                                                            H  H         HCl salt                20   2,5-dichlorophenyl                                                                             CH.sub.2 CON(CH.sub.2 CH.sub.2 OH).sub.2                                                         H  H         HCl salt                21   2,5-dichlorophenyl                                                                             CH.sub.2 CONHCH(CH.sub.2 OH).sub.2                                                               H  H         HI salt                 22   2,5-dichlorophenyl                                                                                                H  H         HBr salt                23   2,5-dichlorophenyl                                                                              ##STR47##         H  H         CF.sub.3 CO.sub.2 H                                                           salt                    24   2,5-dichlorophenyl                                                                              ##STR48##         H  H         HCl salt                25   2,5-dichlorophenyl                                                                              ##STR49##         H  H         HCl salt                26   2,5-dichlorophenyl                                                                             CH.sub.2 CH.sub.2 OPO.sub.3 H.sub.2                                                              H  H         diNa salt               27   2,6-dichloropyridin-4-yl                                                                       CH.sub.2 CH.sub.2 OPO.sub.3 H.sub.2                                                              H  H         diNa salt               28   2,5-dichlorophenyl                                                                             CH.sub.2 CH.sub.2 OSO.sub.3 H                                                                    H  H         HCl salt                29   2,6-dichloropyridin-4-yl                                                                       CH.sub.2 CH.sub.2 OSO.sub.3 H                                                                    H  H         HCl salt                30   2,5-dichlorophenyl                                                                              ##STR50##         H  H         HCl salt                31   2,5-dichlorophenyl                                                                              ##STR51##         H  H         HCl salt                32   2,5-dichlorophenyl                                                                             CH.sub.2 CH.sub.2 OH                                                                             2,6-dimethyl HCl salt                33   2,5-dichlorophenyl                                                                              ##STR52##         H  H         HCl salt                34   2,5-dichlorophenyl                                                                              ##STR53##         H  H         HCl salt                35   2,5-dichlorophenyl                                                                              ##STR54##         H  H         HCl salt                36   2,5-dichlorophenyl                                                                             CH.sub.3           H  NHCOCH.sub.2 NH.sub.2                                                                   zwitterion              __________________________________________________________________________

The ¹ H NMR and FAB MS characterizing properties for the compounds ofExamples 1-35 are shown below in Table I and II.

                  TABLE I                                                         ______________________________________                                        MS DATA                                                                                                 Method                                              Ex. No.    MS             for IV to I                                         ______________________________________                                         1         MH.sup.+  = 556                                                                              1                                                    3         M.sup.+  = 590 1                                                    4         M.sup.+  = 556 1                                                    5         M.sup.+  = 616 1                                                    6         MH.sup.+  =599 1                                                    7         M.sup.+  = 633 1                                                    8         M.sup.+  = 600 1                                                    9         MH.sup.+  = 609                                                                              1                                                   10         MH.sup.+  = 633                                                                              1                                                   11         MH.sup.+  = 582                                                                              1                                                   12         M.sup.+  = 588 1                                                   13         MH.sup.+  = 634                                                                              1                                                   14         MH.sup.+  = 632                                                                              1                                                   15         MH.sup.+  = 586                                                                              2                                                   16         M.sup.+  = 587 2                                                   17         MH.sup.+  = 600                                                                              2                                                   18         MH.sup.+  = 614                                                                              2                                                   19         MH.sup.+  = 616                                                                              2                                                   2          MH.sup.+  = 646                                                                              2                                                   20         M.sup.+  = 687 1                                                   21         MH.sup.+  = 673                                                                              1                                                   22         M.sup.+  = 761 1                                                   23         MH.sup.+  = 761                                                                              1                                                   24         M.sup.+  = 706 2                                                   25         M.sup.+  = 662 2                                                   26         (M.sup.+  + Na) = 688                                                                        2                                                   27         M.sup.+  = 666 2                                                   28         (MH.sup.+  - SO.sub.3) = 586                                                                 2                                                   29         (M.sup.+  - H) = 665                                                                         2                                                   30         M.sup.+  = 678 2                                                   31         M.sup.+  = 646 2                                                   32         MH.sup.+  = 614                                                                              2                                                   33         M.sup.+  = 663 2                                                   34         MH.sup.+  = 692                                                                              2                                                   35         M.sup.+  = 772 2                                                   36         MH.sup.+  = 628                                                                              1                                                   ______________________________________                                    

    TABLE 2      - NMR DATA      ##STR55##                                                                              C     pd. of      Ex. No. H-2 H-6 H-7 H-3' H-7' NH ArH SPyrH R       1 3.49(d, J=18) 5.13(d, J=5) 5.68(dd, J=5, 8) 4.37(s) 3.91(s) 9.28(d,     J=8) 7.23(dd, J=2, 8) 7.98(d, J=7) 4.17(s)       3.73(d, J=18)      7.46-7.49(m) 8.70(d, J=7)       3 3.48(d, J=18) 5.12(d, J=5) 5.66(dd, J=5, 8) 4.36(d, J=14) 3.94(s)     9.28(d, J=8) 7.67(s) 7.99(d, J=7) 4.17(s)       3.73(d, J=18)   4.40(d, J=14)   7.85(s) 8.69(d, J=7)       4 3.48(d, J=18) 5.13(d, J=5) 5.68(dd, J=5, 8) 4.38(t, J=13) 4.00(s)     9.29(d, J=8) 7.51(s) 7.98(d, J=7) 4.17(s)       3.74(d, J=18)       8.68(d, J=7)       5 3.50(d, J=18) 5.13(d, J=5) 5.68(dd, J=5, 8) 4.38(br s) 3.93(s)     9.25(d, J=8) 7.66(s) 8.02(d, J=6) 5.09(d, J=5)       3.74(d, J=18)      7.84(s) 8.71(d, J=6) 5.30-5.42(m)               6.10(m)       6 3.52(d, J=18) 5.14(d, J=5) 5.68(dd, J=5, 8) 4.36(d, J=13) 3.91(s)     9.28(d, J=8) 7.23(dd, J=2, 8) 8.03(d, J=7) 8.01(s)       3.75(d, J=18)   4.44(d, J=13)   7.46-7.49(m) 8.64(d, J=7) 7.66(s)                    5.21(s)       7 3.49(d, J=18) 5.09(d, J=5) 5.62(dd, J=5, 8) 4.37(d, J=13) 3.93(s)     9.27(d, J=8) 7.67(s) 8.10(d, J=7) 5.23(s)       3.69(d, J=18)   4.50(d, J=13)   7.84(s) 8.64(d, J=7)       8 3.51(d, J=18) 5.13(d, J=5) 5.68(dd, J=5, 8) 4.35(d, J=10) 3.99(s)     9.29(d, J=8) 7.50(s) 8.03(d, J=7) 5.19(s)       3.74(d, J=18)   4.44(d, J=10)    8.63(d, J=7)       9 3.44(d, J=18) 5.03(d, J=5) 5.54(dd, J=5, 8) 4.32(d, J=13) 3.75(d,     J=15) 9.12(d, J=8) 7.22(t, J=8) 8.25(d, J=7) 5.18(s, 2H)       3.61(d, J=18)   4.60(d, J=14) 3.82(d, J=15)  7.29-7.36(m) 8.59(d, J=7)     7.65(s, 1H)             7.54(t, J=2)  7.99(s, 1H)      10 3.52(d, J=18) 5.13(d, J=5) 5.67(dd, J=5, 8) 4.37(d, J=13) 3.98(s)     9.33(d, J=8) 7.52(dd, J=1, 8) 8.04(d, J=7) 5.28(s, 2H)       3.74(d, J=18)   4.44(d, J=13)   7.66-7.69(m) 8.69(d, J=7) 7.78(s, 1H)                8.19(s, 1H)      11 3.51(d, J=18) 5.09(d, J=5) 5.63(dd, J=5, 8) 4.35(d, J=13) 3.83(s)     9.20(d, J=8) 7.45(t, J=8) 8.10(d, J=8) 5.22(s)       3.69(d, J=18)   4.49(d, J=13)   7.58(m) 8.64(d, J=7) 7.64(s)             7.79(d, J=8)  8.08(m)             8.20(m)             8.93(m)      12 3.52(d, J=18) 5.12(d, J=5) 5.69(dd, J=5, 8) 4.35(d, J=13) 4.22(s)     9.35(d, J=8) 7.34(t, J=8) 8.07(d, J=7) 5.24(s)       3.72(d, J=18)   4.46(d, J=13)   7.44(t, J=8) 8.66(d, J=7) 7.65(s)                  7.83(d, J=8)  8.12(s)             7.89(d, J=8)      13 3.54(d, J=18) 5.15(d, J=5) 5.70(dd, J=5, 8) 4.36(d, J=13) 4.02(s)     9.25(d, J=8) 8.35(s) 8.02(d, J=7, 5.21(s)       3.76(d, J=18)   4.43(d, J=13)    overlaps with R) 8.01(s, overlaps                  8.65(d, J=7) with SPyrH)               7.66(s)      14 3.53(d, J=18) 5.14(d, J=5) 5.69(dd, J=5, 8) 4.40(t, J=13) 3.93(s)     9.27(d, J=8) 7.66(s) 8.04(d, J=7) 2.27(s)       3.76(d, J=18)      7.85(s) 8.50(d, J=7) 5.54(s)      15 3.51(d, J=18) 5.14(d, J=5) 5.68(dd, J=5, 8) 4.36(d, J=13) 3.99(s)     9.29(d, J=8) 7.24(dd, J=2, 8) 8.01(d, J=7) 3.78(m)       3.68(d, J=18)   4.42(d, J=13)   7.47(m) 8.72(d, J=7) 4.50(m)      16 3.48(d, J=18) 5.11(d, J=5) 5.65(dd, J=5, 8) 4.35(d, J=13) 3.99(s)     9.30(d, J=8) 7.50(s) 8.02(d, J=7) 3.78(m)       3.72(d, J=18)   4.42(d, J=13)    8.69(d, J=7) 4.48(m)      17 3.50(d, J=18) 5.12(d, J=5) 5.67(dd, J=5, 8) 4.37(t, J=13) 3.92(s)     9.31(d, J=8) 7.22(dd, J=2, 8) 7.99(d, J=7) 2.00(m)       3.74(d, J=18)      7.43-7.47(m) 8.81(d, J=7) 3.41(m)               4.52(t, J=7)      18 3.50(d, J=18) 5.12(d, J=5) 5.67(dd, J=5, 8) 4.38(t, J=13) 3.92(s)     9.31(d, J=8) 7.22(dd, J=2, 8) 8.01(d, J=7) 1.38(m)       3.74(d, J=18)      7.43-7.47(m) 8.84(d, J=7) 1.88(m)               3.39(t, J=6)               4.47(t, J=7)      19 3.54(d, J=18) 5.15(d, J=5) 5.69(dd, J=5, 8) 4.38(d, J=13) 3.92(s)     9.31(d, J=8) 7.23(dd, J=2, 8) 8.03(d, J=7) 3.84(br s)       3.76(d, J=18)   4.45(d, J=13)   7.44-7.47(m) 8.81(d, J=7) 4.67-4.77(m)               5.43(br s)      2 3.53(d, J=18) 5.13(d, J=5) 5.67(dd, J=5, 8, 4.38(d, J=13) 3.92-3.93(m,      9.30(d, J=8) 7.23(dd, J=2, 8) 7.98(d, J=7) 3.92-3.93(m,       3.75(d, J=17)  overlaps with R) 4.45(d, J=13) overlaps with R)     7.44-7.48(m) 8.85(d, J=7) overlaps with H-7')               5.50-5.81(br s,               overlaps with H-7)      20 3.61(d, J=18) 5.15(d, J=5) 5.71-5.67(m, 4.38(d, J=13) 3.92(s)     9.29(d, J=8) 7.24(dd, J=2, 8) 8.04(d, J=7) 3.01(br s)       3.77(d, J=18)  overlaps with R) 4.44(d, J=13)   7.46-7.49(m) 8.64(d,     J=7) 3.27(br s)               3.36(m)               3.49(m)               3.63(m)               5.67(s, overlaps               with H-7)      21 3.49(d, J=17) 5.10(d, J=5) 5.63(dd, J=5, 8) 4.37(d, J=13) 3.90(s)     9.26(d, J=8) 7.22(d, J=7) 8.07(d, J=6) 3.43-3.45(m,       overlaps with R)   4.48(d, J=13)   7.43-7.46(m) 8.60(d, J=6) overlaps     with H-2)       3.70(d, J=17,        3.67-3.72(m,       overlaps with R)        overlaps with H-2)               4.75(br s)               8.49(d, J=7)      22 3.36-3.50(m, 5.08(d, J=5) 5.61(dd, J=5, 8) 4.40(d, J=13) 3.88(s)     9.25(d, J=8) 7.23(dd, J=2, 8) 8.06(d, J=6) 3.50-3.36(m,       overlaps with R)   4.46(d, J=13)   7.45(m) 8.62(br s) overlaps with     H-2)               3.67(s)               4.66(t, J=9)               5.26(br s)               9.39(d, J=8)      23 3.45(d, J=18) 5.05(d, J=5) 5.32(m) 3.92(d, J=15) 3.90(s) 9.28(d,     J=8) 7.23-7.19(m) 8.05(d, J=7, 3.67-3.42(m)       3.65(d, J=18)  5.59(dd, J=5, 8) 4.01(d, J=15)   7.51-7.43(m) from one     anomer) 4.23-4.44(m)              7.98(d, J=7, 4.95(s), 5.16 (s)              from one anomer) 4.95(br s), 6.64(s)              8.50-8.60(m) 9.48(d, J=8)      24 3.50-3.70(m, 5.13(d, J=5) 5.69(dd, J=5, 8) 4.37(br s) 3.91(br s)     9.28(d, J=8) 7.23(dd, J=2, 8) 7.97(d, J=7) 3.40-3.80(m,       overlaps with R)      7.45(d, J=8) 8.68(d, J=7) overlaps with H-2)                 7.47(d, J=2)  4.35(d, J=11)               4.67(d, J=11)      25 3.47(d, J=18) 5.13(d, J=5) 5.69(dd, J=5, 8) 4.37(m) 3.94(s) 9.27(d,     J=8) 7.24(m) 8.00(d, J=7) 3.18(m)       3.73(d, J=18)      7.47(m) 8.65(d, J=7) 4.62(m)               6.68(d, J=7)               6.98(d, J=7)      26 3.28(d, J=18) 4.95(d, J=5) 5.46(d, J=5) 4.07(d, J=14) 3.76(d, J=16)     Exchanged 7.16(dd, J=2, 8) 7.73(d, J=7) 4.09(m)       3.56(d, J=18)   4.32(d, J=14) 3.85(d, J=16) (D.sub.2 O) 7.29(d, J=2)     8.42(d, J=7) 4.55(m)             7.32-7.35(m)      27 3.35(d, J=18) 4.99(d, J=5) 5.50(d, J=5) 4.16(d, J=13) 3.93(d, J=10)     Exchanged 7.29(d, J=2) 7.74(d, J=7) 4.08(m)       3.60(d, J=18)   4.33(d, J=13) 3.98(d, J=10) (D.sub.2 O)  8.43(d, J=7)     4.54(m)      28 3.52(d, J=18) 5.13(d, J=5) 5.69(dd, J=5, 8) 4.34(d, J=13) 3.90(s)     9.27(d, J=8) 7.23(dd, J=2, 8) 8.00(d, J=7) 4.16(m)       3.74(d, J=18)   4.40(d, J=13)   7.43-7.46(m) 8.71(d, J=7) 4.63(m)           29 3.52(d, J=18) 5.13(d, J=5) 5.68(dd, J=5, 8) 4.34(d, J=13)     3.99(s) 9.29(d, J=8) 7.49(s) 8.00(d, J=7) 4.16(m)       3.74(d, J=18)   4.40(d, J=13)    8.70(d, J=7) 4.64(m)      30 3.49(d, J=18) 5.13(d, J=5) 5.69(dd, J=5, 8) 4.36(br, s) 3.94(s)     9.30(d, J=8) 7.28-7.30(m) 8.00(d, J=7) 3.04(m)       3.71(d, J=18)      7.41-7.44(m) 8.63(d, J=7) 4.49(m)               6.62-6.65(m)      31 3.52(d, J=18) 5.13(d, J=5) 5.66(dd, J=5, 8) 4.38(br, s) 3.92(s)     9.30(d, J=8) 7.18-7.29(m, 8.00(d, J=7) 3.22(t, J=8)       3.61(d, J=18)      overlaps with R) 8.66(d, J=7) 4.70(t, J=8)             7.45-7.51(m)  7.18-7.29(m,               overlaps with ArH)      32 3.50(d, J=18) 5.13(d, J=5) 5.67(dd, J=5, 8) 4.33(d, J=13) 3.92(s)     9.31(d, J=8) 7.22(dd, J=2, 8) 2.75(s, PyrCH.sub.3) 3.69(m)       3.74(d, J=18)   4.39(d, J=13)   7.45(d, J=8) 7.79(s) 4.48(m)             7.47(d, J=2)      33 3.49(d, J=18) 5.13(d, J=5) 5.68(dd, J=5, 8) 4.38(br s) 39.2(s)     9.28(d, J=8) 7.24(dd, J=2, 8) 8.00(d, J=7) 3.08(m)       3.73(d, J=18)      7.49(m) 8.65(d, J=7) 7.00(m)               9.62(m)      34 3.45(s) 5.12(d, J=5) 5.67(m) 4.37(s) 3.93(s) 9.33(d, J=8) 7.23(dd,     J=2, 8) 7.98(d, J=6) 3.06(t, J=7)       3.51(s)      7.46(d, J=8) 8.71(d, J=6) 3.70(s, 3H)             7.47(d, J=2)  4.67(t, J=7)               6.51(dd, J=2, 8)               6.67(d, J=8)               6.81(d, J=2)      35 3.42(d, J=18) 5.08(d, J=5) 5.62(dd, J=5, 8) 4.40(br s) 3.92(s)     9.28(d, J=8) 7.23(dd, J=2, 8) 8.06(d, J=7) 3.09(m)       3.65(d, J=18)      7.45-7.50(m) 8.64(d, J=7) 3.69(s)               4.63(m)               6.44(s)      36 3.33(d, J=17) 5.00(d, J=5) 5.54(dd, J=5, 8) 4.39(br s) 3.90(s)     9.19(d, J=8) 7.23(dd, J=2, 9) 8.22(d, J=6) 4.19(s)       3.56(d, J=17)      7.45-7.48(m) 8.53(d, J=6)              8.88(d, J=6)              3.80(s, NHCOCH.sub.2      NH.sub.2)

We claim:
 1. A compound having the formula ##STR56## wherein Ar is anaryl group selected from the group consisting of ##STR57## in which R⁴,R⁵, and R⁶ are each independently hydrogen, halogen, trihalomethyl,nitro, C₁ -C₆ alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is aninteger of from 1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is selectedfrom the group consisting of --CR⁸ R⁹ R¹⁰, --(CH₂)_(n) CONR⁸ R⁹ and--(CH₂)_(n) COR⁸ in which R⁸, R⁹ and R¹⁰ are each independentlyhydrogen, substituted or unsubstituted C₁ -C₁₅ alkyl, C₂ -C₁₅ alkenyl orC₂ -C₁₅ alkynyl, substituted or unsubstituted phenyl, phenyl(C₁-C₆)alkyl, naphthyl or naphthyl(C₁ -C₆)alkyl or a sugar moiety of theformula ##STR58## in which said alkyl, alkenyl or alkynyl group, or thealkyl portion of said phenyl(C₁ -C₆)alkyl or naphthyl(C₁ -C₆)alkyl groupcan be substituted by one or more hydroxy groups and said phenyl ornaphthyl group, or the phenyl or naphthyl portion of said phenyl(C₁-C₆)alkyl or naphthyl(C₁ -C₆)alkyl group can be substituted by one ormore hydroxy, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halo or halo(C₁ -C₆)alkylgroups; n is as defined above; R² and R³ are each independentlyhydrogen, C₁ -C₆ alkyl, or amino(C₁ -C₆)alkylcarbonylamino; and R¹¹ ishydrogen, an anionic charge or a carboxyl-protecting group, providedthat when R¹¹ is hydrogen or a protecting group, there is also present acounter ion; or a pharmaceutically acceptable salt or prodrug thereof.2. A compound of claim 1 wherein Ar is ##STR59## in which R⁴, R⁵ and R⁶are each independently hydrogen, halogen, trifluoromethyl or C₁ -C₆alkyl.
 3. A compound having the formula ##STR60## wherein Ar is an arylgroup selected from the group consisting of ##STR61## in which R⁴, R⁵,and R⁶ are each independently hydrogen, halogen, trihalomethyl, nitro,C₁ -C₆ alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer offrom 1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is --CR⁸ R⁹ R¹⁰ in whichR⁸, R⁹ and R¹⁰ are each independently hydrogen, C₁ -C₆ alkyl, hydroxy(C₁-C₆)alkyl, C₂ -C₆ alkenyl, phenyl(C₁ -C₆)alkyl, hydroxyphenyl(C₁-C₆)alkyl or dihydroxyphenyl(C₁ -C₆)alkyl; R² and R³ are eachindependently hydrogen, C₁ -C₆ alkyl or amino (C₁-C₆)alkylcarbonylamino; and R¹¹ is hydrogen, an anionic charge or acarboxyl-protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt or prodrug thereof.
 4. A compound ofclaim 3 wherein Ar is ##STR62## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.
 5. Acompound having the formula ##STR63## wherein Ar is an aryl groupselected from the group consisting of ##STR64## in which R⁴, R⁵, and R⁶are each independently hydrogen, halogen, trihalomethyl, nitro, C₁ -C₆alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is --(CH₂)_(n) CONR⁸ R⁹ in whichR⁸ and R⁹ are each independently hydrogen, hydroxy (C₁ -C₆)alkyl,##STR65## n is as defined above; R² and R³ are each independentlyhydrogen, C₁ -C₆ alkyl or amino (C₁ -C₆)alkylcarbonylamino; and R¹¹ ishydrogen or a protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt or prodrug thereof.
 6. A compound ofclaim 5 wherein R¹ is ##STR66##
 7. A compound having the formula##STR67## wherein Ar is an aryl group selected from the group consistingof ##STR68## in which R⁴, R⁵, and R⁶ are each independently hydrogen,halogen, trihalomethyl, nitro, C₁ -C₆ alkyl, --(CH₂)_(n) OR⁷ or--(CH₂)_(n) SR⁷ ; n is an integer of from 1 to 6; R⁷ is hydrogen or C₁-C₆ alkyl; R¹ is --(CH₂)_(n) COR⁸ in which R⁸ is C₁ -C₆ alkyl; n is asdefined above; R² and R³ are each independently hydrogen, C₁ -C₆ alkylor amino(C₁ -C₆)alkylcarbonylamino; and R¹¹ is hydrogen, an anioniccharge or a carboxyl-protecting group, provided that when R¹¹ ishydrogen or a protecting group, there is also present a counter ion; ora pharmaceutically acceptable salt or prodrug thereof.
 8. A compound ofclaim 7 wherein Ar is ##STR69## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.
 9. Acompound having the formula ##STR70## wherein Ar is an aryl groupselected from the group consisting of ##STR71## in which R⁴, R⁵, and R⁶are each independently hydrogen, halogen, trihalomethyl, nitro, C₁ -C₆alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is ##STR72## R² and R³ are eachindependently hydrogen, C₁ -C₆ alkyl or amino(C₁ -C₆)alkylcarbonylamino;and R¹¹ is hydrogen or a protecting group, provided that when R¹¹ ishydrogen or a protecting group, there is also present a counter ion; ora pharmaceutically acceptable salt or prodrug thereof.
 10. A compound ofclaim 9 wherein Ar is ##STR73## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trifluoromethyl or C₁ -C₆ alkyl.
 11. Acompound selected from the group consistingof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(1-Prop-2-enyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]-methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(1-naphthylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-benzthiazolylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5,6-trichloropyridin-2-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Acetylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(3-Hydroxy-1-propyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(4-Hydroxy-1-butyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-Hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(N,N-di-2-Hydroxyethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-[2-Hydroxy-1-(hydroxymethyl)ethyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-2-[2-Deoxy-D-galactopyranosyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-3-(3-Deoxy-D-glucopyranosyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[1-(1-Deoxy-D-glucitolyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-(4-Hydroxyphenyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Phosphorylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-(3,4-Dihydroxyphenyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-Phenylethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof; and1-Methyl-3-aminomethylcarbonylamino-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl)methylthio)]pyridiniuminner salt or a pharmaceutically acceptable salt thereof.
 12. A compoundselected from the group consistingof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]-methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoro-methylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(1-naphthylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-benzthiazolylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Acetylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Hydroxy-1-ethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(3-Hydroxy-1-propyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl-thio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]-pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(4-Hydroxy-1-butyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-Hydroxy-1-(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-Hydroxy-1,1-di(hydroxymethyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(N,N-di-2-Hydroxyethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-[2-Hydroxy-1-(hydroxymethyl)ethyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-2-[2-Deoxy-D-galactopyranosyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[1-(1-Deoxy-D-glucitolyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-phenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[2-(4-Hydroxyphenyl)ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof; and1-Methyl-3-aminomethylcarbonylamino-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl)methylthio)]pyridiniuminner salt or a pharmaceutically acceptable salt thereof.
 13. A compoundselected from the group consistingof1-Methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-Carbamoylmethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-[2-Hydroxy-1-(hydroxymethyl)ethyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo-[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-2-[2-Deoxy-D-galactopyranosyl]carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[1-(1-Deoxy-D-glucitolyl)]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof; and1-(2-Sulfonylhydroxyethyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methyl-thio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition comprising an effective antibacterial amountof a compound of claim 1 and a pharmaceutically acceptable carrier ordiluent.
 15. A method of treating a bacterial infection which comprisesadministering to a host afflicted with such infection an effectiveantibacterial amount of a compound of claim
 1. 16. A method of treatinga bacterial infection caused by a strain of methicillin-resistantStaphylococcus aureus which comprises administering to a host afflictedwith such infection an effective antibacterial amount of a compound ofclaim 1.